It has not
proven effective in maintaining sleep and is more used for sleep initiation
problems. The fast dissolving oral films were prepared by solvent casting
method using various polymers like HPMC E5, HPMC E15,
HPMC K15, microcrystalline cellulose and poly vinyl alcohol.
Glycerol used as plasticizer (Vinay Umesh Rao et al).
MATERIALS AND METHODS:
Materials:
Zolpidem tartarate (EMCO industries, Hyd) HPMC E5, HPMC E 15, HPMC K15 and Poly vinyl
Alcohol (PVA (Dow Chemicals, USA)
Micro crystalline cellulose, Pregelatinised starch
(S.D fine Chemical .Mumbai) Glycerol (Merck,
India).
Methods: solvent
casting method (Pratikkumar
Joshi et al):
Accurately weighed
quantities of polymers (HPME E5, E15 and k15) were dissolved in distilled
water. The solution was heated and bubble free, to this plasticizer,(glycerol)
and sweetener, (mannitol) were added and mixed thoroughly, drug was added to
above solution and dissolve completely, now clear solution was poured into
clean Petri dish. It was dried in hot
air oven up to 24 hours then peeled off from the Petri dish stored in
desiccators for further study.
Evaluation
of fast dissolving oral films:
1.
Percentage elongation and tensile strength (Buchi N et al) :
The films were cut into a size of 2cm x 2cm
strips. One end of the strip along its
length was clamped to the tensile strength testing apparatus and the other end
was attached to a movable rod. The movable rod was attached to a pan with the
help of a non-stretchable string through a pulley. Weights were carefully added onto the pan and
the weight was gradually increased. The
elongation of the patch was determined by measuring the distance moved by the
pointer (on a graph paper) after the addition of the weight each time. The
weights were added, until the film was cut.
Percentage elongation was
determined using the formula,(Lw -L)
Percentage
elongation at break point = (Lw – L) x 100
L
The tensile strength of the patch was
determined using the formula,
Where,
a = width (cm), b =thickness (cm), l
=length of the test patch strip (cm), Dl = elongation at the break point (cm) and W
= weight required to break the patch (g)
2. Folding endurance
The folding endurance was measured manually for the prepared films.
A strip of film 2x2cm
was cut evenly and repeatedly folded
at
the same place till it broke. The number of times the film could be folded at the
same place without breaking gave
the exact value
of folding endurance.
3. Thickness:
Precise film thickness measurements were
carried out using NIKON DigiMicro encoders/gauges (Nanowave Inc. MA 01590 USA, MF501–50 mm travel range along
with TC-101) that are used in motion control systems with optical linear
encoder heads with a specially developed MPM300-OEM motion processing module
providing nanometer resolution. These encoder/gauge heads were used with the
Nikon TC-101 interpolator-counter with digital read-out. The encoders use a 12
volt direct current (VDC) power supply. Thickness was measured at four corners
and in the centre of the selected film.
4. Determination of moisture content:
The prepared films were weighed and kept in
a vacuum desiccator containing anhydrous silica at
room temperature. The patches were weighed repeatedly until they showed a
constant weight. Percent moisture content was
determined using the formula,
% Moisture
Content =
(Initial weight of the film – Final weight of the
film) x 100
Initial
weight of the film
5. Determination of moisture up
take (M.K. Patidar et al) :
The prepared
films were weighed and kept in a desiccators containing anhydrous silica at
room temperature for 24 hours. It was then taken out from the desiccator, weighed and exposed to
relative humidity of 75% (saturated solution of sodium chloride) in
desiccators. The film was weighed until it showed a constant weight. Percent
moisture uptake was determined using the formula.
% Moisture
Uptake =
(Final weight of the film – Initial weight of the film) x 100
Initial weight of the film
6. Drug content:
Six films of each formulation were used.
Films were cut into small pieces and transferred into a glass mortar. About 10 mL of
water was added and triturated for 30 min.
The contents were transferred into 100 mL
volumetric flask. The mortar was rinsed
three times with each 15 mL of water and the rinsed
portions were transferred to a volumetric flask. The solution was shaken continuously for one
hour. It was then heated on a steam bath for 10 min and cooled to room
temperature. Fifty milliliters of water
was added and the volume was made up with water. The solution was filtered through Whatman-1
filter paper and the drug content in the resultant solution was determined by
measuring the absorbance at 293 nm.
7.
Disintegration tests (Sandeep Saini et al):
Disintegration refers to the physical
process by which a film dissolves into a solution. Disintegration times were
measured in vitro for six samples by the standard United States
Pharmacopeia (USP) disintegration method in artificial saliva at 37°C using the
disintegration apparatus (Electrolab, ED-2L, Mumbai,
INDIA). The time required for full disintegration was recorded for each film.
8. In vitro dissolution studies (S. Raju et al):
In vitro dissolution test was carried out according to the USP
II paddle dissolution apparatus. The test solution was 900 mL
of 6.8pH phosphate buffer at 37±0.5°C and the rotation rate of 75
rpm. 5 mL sample of the dissolution medium was
withdrawn at regular time intervals.
After each withdrawal, an equal volume of dissolution medium was
replaced. The absorbance was measured at
295 nm and the percent drug released was calculated.
9.
Stability studies:
Stability studies on selected formulations
were conducted according to International Conference on Harmonization (ICH)
guidelines. Stability studies were carried out for the best films, stored in an
aluminum package in a chamber (Electrolab) controlled
at 40°C and 75% in humidity for 3 months. The content of ZT was then determined
spectrophotometrically as described earlier. The films were also subjected to
other physical and dissolution tests.
RESULTS AND DISCUSSIONS:
Evaluation parameters fast dissolving
oral films:
Disintegration time:
Table
No 2: Disintegration times of different batches of
prepared oral thin films
|
Formulation
codes |
Disintegration
time (sec) |
|
F1 |
49 |
|
F2 |
90 |
|
F3 |
No film |
|
F4 |
57 |
|
F5 |
85 |
|
F6 |
No film |
|
F7 |
23 |
|
F8 |
47 |
Totally 8 batches of films were prepared to
optimize the formulation (F1 to F8). Among these F1, F4, F7 and F8 showed best
formulations based on the disintegration studies. The disintegration time of
the developed oral thin films are shown in Table the data reveal that all the
formulations, except F2, F3, F5 and F8 disintegrated within 60 sec and hence
omitted for further studies, as it did not meet the criteria of oral thin films
according to which disintegration should take place in less than a minute.
Physical
parameters:
Table
No 3: Physical properties of the prepared oral thin films
|
Formulation Codes |
Thickness of patch (µm) |
Tensile strength, (N/m2) |
Elongation (%) |
|
FI |
39±0.01 |
1.689±0.18 |
9.3±0.65 |
|
F4 |
43±0.02 |
1.865±0.23 |
10.1±0.59 |
|
F7 |
56±0.01 |
1.72±0.78 |
10.3±0.62 |
|
F8 |
67±0.03 |
2.13±0.65 |
11.2±0.12 |
Table No 4: Moisture studies and content uniformity of the
prepared oral thin films
|
Formulation Codes |
Moisture content (%) |
Moisture uptake (%) |
Drug content (%) |
|
FI |
2.89±0.05 |
2.85±0.05 |
92.6±1.1 |
|
F4 |
3.01±0.11 |
3.12±0.09 |
93.8±2.1 |
|
F7 |
3.23±0.25 |
3.23±0.35 |
91.6±1.12 |
|
F8 |
3.12±0.68 |
3.31±0.76 |
97.8±1.74 |
DISCUSSION:
The tensile strength of each film was
determined and the data obtained is given in Table no 3. The data reveal that
tensile strength varies from 1.8-2.2 N/m2.Addition of polymers and
increase in polymer weight/ratio shows a significant increase in the tensile
strength. The data indicates that as the concentration of polymer increases
thickness increases. Thickness is
directly proportional to tensile strength. In other words as thickness
increases tensile strength also increases. The data obtained for
moisture absorption are given in Table. No 4 As the concentration of polymer
increases, the percent moisture absorption increases. Low moisture content ensures stability and prevents
the formation of dried and brittle films. The moisture uptake of the
formulations indicates that in high humid environment, the patches take up very
little moisture (1-2%). This may favors the stability as well as compatibility
with high humid conditions of the formulations. The drug content of the
prepared films was in the range of 92-98%.
Fig No 1: In
vitro dissolution studies of the prepared oral thin films of Zolpidem
DISCUSSION:
The in vitro drug release data indicate that batch F7 shows highest
drug release compared to all other formulations. Therefore F7 batch was studied
for further studies. For F7 formulation conducted stability studies as per ICH
guide lines
Stability
studies:
Table
No 5: Physical
properties of the prepared oral thin film of F7 (stability studies)
|
Time (days) |
Elongation (%) |
Tensile strength, (N/m2) |
Thickness of patch (µm) |
|
0 |
11.2±0.11 |
1.79±0.25 |
48±0.01 |
|
30 |
11.2±0.21 |
1.783±0.33 |
48±0.02 |
|
60 |
10.9±0.78 |
1.79±0.43 |
49±0.01 |
|
90 |
10.7±1.2 |
1.778±0.56 |
48±0.01 |
Table No 6: Moisture studies and content uniformity of the prepared
oral thin films of F7 (stability studies)
|
Time (days)
|
Moisture content (%)
|
Moisture uptake (%)
|
Drug content (%)
|
|
0 |
3.01±0.09 |
3.13±0.07 |
92.5±0.9 |
|
30 |
3.01±0.22 |
3.13±0.09 |
91.8±1.2 |
|
60 |
3.01±0.1 |
3.13±0.05 |
91.5±1.5 |
|
90 |
3.01±0.13 |
3.13±0.03 |
92.1±1.3 |
From the investigation it was found that
the formulations were satisfactorily stable up to 3 months at 40ºC ±2ºC 75% RH.
During storage drug content, pH, drug release and other parameters were
observed. Films were transparent and were no change in color. The results from
the Table: 5-6 indicate that prepared films were stable.
CONCLUSION:
From the present investigation, the
obtained result concludes that the drug delivery systems of ZT were designed
using different polymers and evaluated in
vitro. The oral thin films were prepared by the coating solvent casting
method. The prepared films were evaluated for thickness, elongation (%),
moisture studies, content uniformity, in
vitro dissolution and pharmacokinetic parameters. The following are some of
the important conclusions made from the present study; the data on the physical
parameters generated are such as thickness, moisture content, moisture uptake
and surface flatness are found to be favorable for the development of oral thin
films. Oral thin films developed show acceptable physical properties and rapid
desirable disintegration. The in vitro
results reveal that the F7 formulation releases the drug immediately compared
to other formulations. The formulation F7 was found to be stable, since no
significant changes in drug release, content uniformity and other physical
properties are observed. These present findings, suggest that the oral thin
film containing ZT developed disintegrate within a minute and hence is
potentially useful in managing the INSOMNIA and in patients suffering from
dysphasia or aphasia and also in the case of geriatric patients who show
unwillingness to take tablets.
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Received on 16.03.2016 Accepted on 08.04.2016
© Asian Pharma
Press All Right Reserved
Asian J. Pharm.
Res. 2016; 6(2): 67-71
DOI: 10.5958/2231-5691.2016.00012.5